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Chemical Compound Review

AGN-PC-0084PA     methylphosphonic acid

Synonyms: CHEMBL122938, AG-I-01423, ACMC-20ake9, CHEBI:45129, HSDB 6762, ...
 
 
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Disease relevance of methylphosphonic acid

 

High impact information on methylphosphonic acid

  • The approximately 30,000-fold acceleration in the rate of hydrolysis of a methylphosphonate versus phosphodiester suggests that repulsion of water by the DNA phosphate anion suppresses the latent nuclease function of topoisomerase IB [4].
  • The dodecamer d(TpTCCTCCTGCGG) (deoxynucleoside methylphosphonate residues in italic) caused 50% and 98% decreases in herpes simplex virus type 1 titers at concentrations of 15 microM and 100 microM, respectively. d(TpTCCTCCTGCGG) inhibited viral but not cellular protein synthesis and decreased splicing of immediate early pre-mRNAs 4 and 5 [5].
  • Mcl-1 expression was specifically disrupted by chimeric methylphosphonate/phosphodiester antisense oligodeoxynucleotides to just 5% of control levels [6].
  • Liposomal delivery of methylphosphonate antisense oligodeoxynucleotides in chronic myelogenous leukemia [7].
  • This is the first demonstration of sequence-specific antisense DNA methylphosphonate inhibition of gene expression in the bloodstream of an animal model [8].
 

Chemical compound and disease context of methylphosphonic acid

 

Biological context of methylphosphonic acid

 

Anatomical context of methylphosphonic acid

  • Biotinylated antisense methylphosphonate oligodeoxynucleotides. Inhibition of spliceosome assembly and affinity selection of U1 and U2 small nuclear RNPs [19].
  • Uptake of phosphodiester oligonucleotides, but not of methylphosphonate oligonucleotides, could be blocked by acidification of the cytosol [17].
  • Antisense oligonucleotides containing either anionic diester or neutral methylphosphonate internucleoside linkages were prepared by automated synthesis, and were compared for their ability to arrest translation of human dihydrofolate reductase (DHFR) mRNA in a nuclease treated rabbit reticulocyte lysate [20].
  • Permeation characteristics of 32P or fluorescent labelled methylphosphonate (MP-oligo), phosphorothioate (S-oligo), alternating methylphosphonate-phosphodiester (Alt-MP) and unmodified phosphodiester (D-oligo) oligodeoxynucleotides were studied using liposomal membranes [21].
  • Likewise, accumulation of the Pho84 protein at the plasma membrane of the same cells is inhibited by methylphosphonate, although the derepressive expression of the PHO84 gene is unperturbed [22].
 

Associations of methylphosphonic acid with other chemical compounds

  • To further refine the model, 5' flap endonuclease variants with alanine point substitutions at amino acid residues expected to contact phosphates in the substrate and one deletion mutant were tested in enzyme activity assays on the methylphosphonate-modified substrates [23].
  • Dimethyl methylphosphonate (DMMP), when added to a suspension of erythrocytes, has been reported to have a lower frequency chemical shift inside of cells than outside [24].
  • Effects of methylphosphonate, a phosphate analogue, on the expression and degradation of the high-affinity phosphate transporter Pho84, in Saccharomyces cerevisiae [22].
  • Conformational heterogeneity was confirmed with the methylphosphonate ester anion adduct of the active-site serine, which showed two deshielded resonances of equal intensity at 16.5 and 15.8 ppm with phi values of 0.47 +/- 0.10 and 0.49 +/- 0.10 corresponding to average hydrogen bond lengths of 2.59 +/- 0.04 and 2.61 +/- 0.04 A, respectively [25].
  • The chain lengths of the oligomers were confirmed after 5'-end labeling with polynucleotide kinase by partial hydrolysis of the methylphosphonate linkages with 1 M aqueous piperidine followed by polyacrylamide gel electrophoresis of the hydrolysate.(ABSTRACT TRUNCATED AT 250 WORDS)[26]
 

Gene context of methylphosphonic acid

  • However, the presence of methylphosphonate under such conditions represses the Pho5 acidic phosphatase activity of PHO84 cells, a finding that implies a direct role of the analogue in the regulation of phosphate-responsive genes and/or proteins [22].
  • At P106, only the Rp methylphosphonate isomer is impaired in rev binding ability and it is proposed that the Rp oxygen is hydrogen-bonded to an uncharged amino acid or to a main chain hydrogen atom [14].
  • Synthesis and in vitro properties of a powerful quaternary methylphosphonate inhibitor of acetylcholinesterase. A new marker in blood-brain barrier research [27].
  • Reversible modification of tissue-type plasminogen activator by methylphosphonate esters [28].
  • Methylphosphonate (PC) backbone oligodeoxynucleotides complementary to the 5'-terminal nucleotides of U1 and U2 small nuclear (sn) RNAs do not elicit RNase H action under conditions in which natural (phosphodiester) oligodeoxynucleotides yield extensive RNase H cleavage [19].
 

Analytical, diagnostic and therapeutic context of methylphosphonic acid

  • The nuclease stability and ability of the methylphosphonate oligomers to form stable complexes with their target nucleic acids suggest that these oligomers are potential candidates for use as antisense or antigene agents in cell culture [29].
  • A 12-mer oligodeoxynucleotide containing 10 methylphosphonate bonds and 1 phosphodiester bond was shown to bind specifically to the restriction endonuclease fragment containing complementary DNA in a Southern blot [30].
  • Rapid and specific recognition of methylphosphonic acid (MPA), the degradation product of nerve agents sarin, soman, VX, etc., was achieved with potentiometric measurements using a chemical sensor fabricated by a surface imprinting technique coupled with a nanoscale transducer, indium tin oxide (ITO) [31].
  • Since MP is the final degradation product of many nerve agents, these PhnD conjugates can function as components in a biosensor system for chemical warfare agents [32].
  • Antisense DNA oligonucleotides. II: The use of matrix-assisted laser desorption/ionization mass spectrometry for the sequence verification of methylphosphonate oligodeoxyribonucleotides [33].

References

  1. Inhibition of acquired immunodeficiency syndrome virus by oligodeoxynucleoside methylphosphonates. Sarin, P.S., Agrawal, S., Civeira, M.P., Goodchild, J., Ikeuchi, T., Zamecnik, P.C. Proc. Natl. Acad. Sci. U.S.A. (1988) [Pubmed]
  2. pH homeostasis in Escherichia coli: measurement by 31P nuclear magnetic resonance of methylphosphonate and phosphate. Slonczewski, J.L., Rosen, B.P., Alger, J.R., Macnab, R.M. Proc. Natl. Acad. Sci. U.S.A. (1981) [Pubmed]
  3. Antiviral effect of an oligo(nucleoside methylphosphonate) complementary to the splice junction of herpes simplex virus type 1 immediate early pre-mRNAs 4 and 5. Smith, C.C., Aurelian, L., Reddy, M.P., Miller, P.S., Ts'o, P.O. Proc. Natl. Acad. Sci. U.S.A. (1986) [Pubmed]
  4. Guarding the genome: electrostatic repulsion of water by DNA suppresses a potent nuclease activity of topoisomerase IB. Tian, L., Claeboe, C.D., Hecht, S.M., Shuman, S. Mol. Cell (2003) [Pubmed]
  5. Site specificity of the inhibitory effects of oligo(nucleoside methylphosphonate)s complementary to the acceptor splice junction of herpes simplex virus type 1 immediate early mRNA 4. Kulka, M., Smith, C.C., Aurelian, L., Fishelevich, R., Meade, K., Miller, P., Ts'o, P.O. Proc. Natl. Acad. Sci. U.S.A. (1989) [Pubmed]
  6. Apoptosis is rapidly triggered by antisense depletion of MCL-1 in differentiating U937 cells. Moulding, D.A., Giles, R.V., Spiller, D.G., White, M.R., Tidd, D.M., Edwards, S.W. Blood (2000) [Pubmed]
  7. Liposomal delivery of methylphosphonate antisense oligodeoxynucleotides in chronic myelogenous leukemia. Tari, A.M., Tucker, S.D., Deisseroth, A., Lopez-Berestein, G. Blood (1994) [Pubmed]
  8. Down-regulation of c-MYC antigen expression in lymphocytes of Emu-c-myc transgenic mice treated with anti-c-myc DNA methylphosphonates. Wickstrom, E., Bacon, T.A., Wickstrom, E.L. Cancer Res. (1992) [Pubmed]
  9. Induction of chronic human immunodeficiency virus infection is blocked in vitro by a methylphosphonate oligodeoxynucleoside targeted to a U3 enhancer element. Laurence, J., Sikder, S.K., Kulkosky, J., Miller, P., Ts'o, P.O. J. Virol. (1991) [Pubmed]
  10. Mechanism of inhibition of the class C beta-lactamase of Enterobacter cloacae P99 by phosphonate monoesters. Rahil, J., Pratt, R.F. Biochemistry (1992) [Pubmed]
  11. Triplex formation by psoralen-conjugated chimeric oligonucleoside methylphosphonates. Cassidy, R.A., Kondo, N.S., Miller, P.S. Biochemistry (2000) [Pubmed]
  12. Mapping and molecular cloning of the phn (psiD) locus for phosphonate utilization in Escherichia coli. Wanner, B.L., Boline, J.A. J. Bacteriol. (1990) [Pubmed]
  13. Two-generation reproductive study in mink fed diisopropyl methylphosphonate (DIMP). Bucci, T.J., Kovatch, R.M., Mercieca, M.D., Perman, V., Klingensmith, J.S. Reprod. Toxicol. (2003) [Pubmed]
  14. Methylphosphonate mapping of phosphate contacts critical for RNA recognition by the human immunodeficiency virus tat and rev proteins. Pritchard, C.E., Grasby, J.A., Hamy, F., Zacharek, A.M., Singh, M., Karn, J., Gait, M.J. Nucleic Acids Res. (1994) [Pubmed]
  15. Synthesis of specific diastereomers of a DNA methylphosphonate heptamer, d(CpCpApApApCpA), and stability of base pairing with the normal DNA octamer d(TPGPTPTPTPGPGPC). Vyazovkina, E.V., Savchenko, E.V., Lokhov, S.G., Engels, J.W., Wickstrom, E., Lebedev, A.V. Nucleic Acids Res. (1994) [Pubmed]
  16. Duplex stabilities of phosphorothioate, methylphosphonate, and RNA analogs of two DNA 14-mers. Kibler-Herzog, L., Zon, G., Uznanski, B., Whittier, G., Wilson, W.D. Nucleic Acids Res. (1991) [Pubmed]
  17. Mechanism of cellular uptake of modified oligodeoxynucleotides containing methylphosphonate linkages. Shoji, Y., Akhtar, S., Periasamy, A., Herman, B., Juliano, R.L. Nucleic Acids Res. (1991) [Pubmed]
  18. Molecular and crystal structure of Sp-thymidin-3'-yl 4-thiothymidin-5'-yl methylphosphonate. Szabó, T., Noréus, D., Norrestam, R., Stawinski, J. Nucleic Acids Res. (1993) [Pubmed]
  19. Biotinylated antisense methylphosphonate oligodeoxynucleotides. Inhibition of spliceosome assembly and affinity selection of U1 and U2 small nuclear RNPs. Temsamani, J., Agrawal, S., Pederson, T. J. Biol. Chem. (1991) [Pubmed]
  20. Comparative hybrid arrest by tandem antisense oligodeoxyribonucleotides or oligodeoxyribonucleoside methylphosphonates in a cell-free system. Maher, L.J., Dolnick, B.J. Nucleic Acids Res. (1988) [Pubmed]
  21. Interactions of antisense DNA oligonucleotide analogs with phospholipid membranes (liposomes). Akhtar, S., Basu, S., Wickstrom, E., Juliano, R.L. Nucleic Acids Res. (1991) [Pubmed]
  22. Effects of methylphosphonate, a phosphate analogue, on the expression and degradation of the high-affinity phosphate transporter Pho84, in Saccharomyces cerevisiae. Pratt, J.R., Mouillon, J.M., Lagerstedt, J.O., Pattison-Granberg, J., Lundh, K.I., Persson, B.L. Biochemistry (2004) [Pubmed]
  23. Modeling of flap endonuclease interactions with DNA substrate. Allawi, H.T., Kaiser, M.W., Onufriev, A.V., Ma, W.P., Brogaard, A.E., Case, D.A., Neri, B.P., Lyamichev, V.I. J. Mol. Biol. (2003) [Pubmed]
  24. Dimethyl methylphosphonate (DMMP): a 31P nuclear magnetic resonance spectroscopic probe of intracellular volume in mammalian cell cultures. Barry, J.A., McGovern, K.A., Lien, Y.H., Ashmore, B., Gillies, R.J. Biochemistry (1993) [Pubmed]
  25. Short, strong hydrogen bonds at the active site of human acetylcholinesterase: proton NMR studies. Massiah, M.A., Viragh, C., Reddy, P.M., Kovach, I.M., Johnson, J., Rosenberry, T.L., Mildvan, A.S. Biochemistry (2001) [Pubmed]
  26. Solid-phase syntheses of oligodeoxyribonucleoside methylphosphonates. Miller, P.S., Reddy, M.P., Murakami, A., Blake, K.R., Lin, S.B., Agris, C.H. Biochemistry (1986) [Pubmed]
  27. Synthesis and in vitro properties of a powerful quaternary methylphosphonate inhibitor of acetylcholinesterase. A new marker in blood-brain barrier research. Levy, D., Ashani, Y. Biochem. Pharmacol. (1986) [Pubmed]
  28. Reversible modification of tissue-type plasminogen activator by methylphosphonate esters. Zhao, O., Kovach, I.M. Bioorg. Med. Chem. (1996) [Pubmed]
  29. Studies on anti-human immunodeficiency virus oligonucleotides that have alternating methylphosphonate/phosphodiester linkages. Miller, P.S., Cassidy, R.A., Hamma, T., Kondo, N.S. Pharmacol. Ther. (2000) [Pubmed]
  30. Effect of ionic strength on the hybridization of oligodeoxynucleotides with reduced charge due to methylphosphonate linkages to unmodified oligodeoxynucleotides containing the complementary sequence. Quartin, R.S., Wetmur, J.G. Biochemistry (1989) [Pubmed]
  31. Potentiometric sensing of chemical warfare agents: surface imprinted polymer integrated with an indium tin oxide electrode. Zhou, Y., Yu, B., Shiu, E., Levon, K. Anal. Chem. (2004) [Pubmed]
  32. Identification of cognate ligands for the Escherichia coli phnD protein product and engineering of a reagentless fluorescent biosensor for phosphonates. Rizk, S.S., Cuneo, M.J., Hellinga, H.W. Protein Sci. (2006) [Pubmed]
  33. Antisense DNA oligonucleotides. II: The use of matrix-assisted laser desorption/ionization mass spectrometry for the sequence verification of methylphosphonate oligodeoxyribonucleotides. Keough, T., Baker, T.R., Dobson, R.L., Lacey, M.P., Riley, T.A., Hasselfield, J.A., Hesselberth, P.E. Rapid Commun. Mass Spectrom. (1993) [Pubmed]
 
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